Intravenous drug use continues to be a major public health problem which has become a significant vector for the spread of AIDS. The combined use cocaine and heroin (speedball) has proven to be a significant challenge for the treatment of cocaine and heroin abuse. This application proposes investigation of the brain processes underlying speedball self- administration. Recent data from the laboratory suggests a potential mechanism for the enhance reinforcing effects of speedball compared to either drug alone that is observed in drug abusers. The self-administration of cocaine/heroin combinations resulted in large increases in the extracellular fluid levels of dopamine ([DA]e) in the nucleus accumbens (Nacc) above that with cocaine self-administration, while heroin self- administered alone has no effect. The research proposed in this application is designed to test the hypothesis that the potentiation of heroin of cocaine's elevation of [DA]e in the Nacc are through opioid receptors perhaps on GABA neurons and this potential is the basis of the enhanced reinforcing effects of speedball. Experiments will initially assess the loci and opioid receptor subtypes necessary for this potential by determining the effects of selective alkylation on the reinforcing efficacy (with progressive ratio schedules) and self-administration thresholds (with fixed ratio schedules) for speedball. Experiments will initially assess the loci and opioid receptor subtypes necessary for this potentiation by determining the effects of selective alkylation on the reinforcing efficacy (with progressive ratio schedules) and self-administration thresholds (with fixed ratio schedules) for speedball. In addition, the association between the dose intake relationship for cocaine and speedball and Nacc [DA]e will be assessed throughout the dose-intake curve. Additional experiments will determine if treatments that attenuate the potentiation of reinforcing efficacy and threshold lowering effects of heroin on self-administered cocaine also attenuate the potentiation of Nacc [CA]e. Experiments will determine whether the potentiation is through opioid receptors that impact GABA releasing neurons by injecting selective GABA agonists and antagonists into identified brain regions and assessing effects on self-administration thresholds; and, if effective, on Nacc [DA]e. In addition, experiments will assess whether direct injections of selective opioid receptor agonists into identified brain regions is sufficient to enhance the reinforcing efficacy and lower thresholds for cocaine self-administration. In this manner, the neurobiological mechanisms of this potentiation can be determined.